The aim of developing infusion solutions which can be administered intravenously is always good tolerability of the preparation. To ensure this it is necessary for the formulation to be approximated as closely as possible to physiological circumstances, that is to say it should be in the form of an aqueous formulation with isotonic (osmolarity) and isohydric (pH) properties.
Some active pharmaceutical ingredients have the disadvantage that they are difficult to formulate or convert into a form ready for use owing to their low solubility, sensitivity to hydrolysis or oxidation or owing to their photosensitivity. This can in the final analysis be attributed to the fact that the active ingredients are not in thermodynamic equilibrium under usual formulating conditions, that is to say that they either precipitate or decompose under physiological conditions. Thus the formulation possibilities and, in the final analysis, the provision of such active ingredients are greatly restricted.
Active pharmaceutical ingredients, especially those of the more recent generation, often have the disadvantage of low solubility in aqueous medium at physiologically tolerated pH values. This applies in particular to active ingredients from the group of dihydropyridines, anaesthetics, antibiotics, antimycotics, immunosuppressants, CNS-active drugs, oncologicals, steroids, barbiturates and vitamins. Slightly soluble active ingredients have, according to the definition in current pharmacopoeias, a solubility in water of less than 1 percent by weight. Slightly soluble active ingredients frequently confront the pharmaceutical technologist with the problem of developing a sufficiently well tolerated aqueous infusion solution when the volume administered by infusion is strictly limited. The patient in particular in intensive care units (ICU) frequently receives several infusion solutions administered in parallel, in which case the acceptable daily volume depends on the kidney function of the individual. One priority of pharmaceutical development is to minimize the infusion volume, this parameter showing a contrary behaviour to the solubility of the substance. Formulating additions such as isotonicizing agents, antioxidants etc. moreover reduce the dissolving capacity of water. The active ingredient also frequently has a solubility or stability optimum outside the physiological pH range of 7.2-7.6, so that the formulation possibility is further restricted at the optimum pH.
Because of the poor solubility in aqueous media, the active ingredient is dissolved in an organic or aqueous/organic solvent or at strongly acidic/alkaline pH values in aqueous or aqueous/organic medium (active ingredient concentrate). In order to ensure tolerability, administration of this active ingredient concentrate must be preceded by dilution with an aqueous medium (diluting medium) or adjustment to physiologically tolerated pH values. This may result in supersaturated solutions. These are characterized in that the dissolved active ingredient is present in a concentration higher than is possible in the solvent at the given temperature by dissolving the active ingredient crystals. Such solutions are, as a consequence of the kinetic inhibition of crystallization, initially optically clear and virtually free of particles. However, the solutions are thermodynamically unstable. Thus, over the course of time, they lead to the active ingredient crystallizing out and thus particles being formed. Since relatively long times, which include at least the duration of the infusion, frequently elapse for example after preparation of such solutions in hospitals until they are completely infused into the patients, formation of particles in the solution is possible during this. Particles injected into the bloodstream may, however, depending on their size and shape lead inter alia to vascular occlusion and thus to serious harm to the patient. This risk can be reduced either by ensuring the stability of the supersaturation also over a lengthy period and under all environmental conditions, demonstrating this with certainty, or by minimizing the time the supersaturated solution stands after its preparation. The latter object is achieved by the present invention, namely by preparing the supersaturated solution from an active ingredient concentrate and a diluting medium with use of a special mixer immediately before administrationxe2x80x94on the patient""s armxe2x80x94and only seconds up to a few minutes elapsing until the solution enters the bloodstream.
On simultaneous parenteral administration of different solutions by intravenous infusion so-called connecting pieces or Y pieces (for example Codan Art. No. C87/2R) have been used to date. Connection to other infusion equipment takes place, for example, via so-called Luer-Lock connectors complying with DIN 13090 Part 2 (disposable medical articles: medical products; standards and other documents; Beuth Verlag 1989). The infusion solutions having viscosities in the region of a few mPas are fed from different containers to the relevant connecting piece and combined therein simply by being conducted together before the mixture reaches the patient. An infusion device of this type is described, for example, in DE-3228595-C2. In this case, 2 solutions from infusion bottles are combined by gravity through a Y piece and infused. Disposable articles of this type are commercially available in a variety of forms. The disadvantage of the available devices is that it is impossible to mix fluid media with very different viscosities at the available low flow rates (5-500 ml/h) sufficiently and quickly enough because the commercially available connecting pieces are not optimal in terms of their function as mixers. In particular at low flow velocities there is sometimes a back-flow of the solutions, and components of the solution spend some time in regions of low flow (dead spaces). This can lead to crystallization inside the administration system. Organic solvents which can be administered parenterally may have viscosities above 100 mPas (for example macrogol 400). When the organic active ingredient concentrate and the aqueous diluting medium are mixed there is a risk that the active ingredient will crystallize out of the supersaturated solution after a certain time. The time up to the onset of crystallization decreases with increasing content of aqueous phase. However, at the same time, the tolerability increases with increasing content of aqueous phase.
The result of the problems described is that no such concentrate/dilution systems have yet been developed for a marketable product. On the contrary, the only solution presentations marketed are those whose system is not supersaturated. This is achieved, for example, by adding relatively large amounts and relatively high concentrations of organic solvents (ethanol, macrogol, propylene glycol etc.) or solubilizers and surfactants (Tween, Cremophor), which have an adverse effect on the local and systemic tolerability of the formulation.
GB-A-1472793 describes such formulations for the anaesthetic propofol, in which surface-active substances and water-miscible, nonaqueous solvents are added to the aqueous base. A concentration of 20-30% of organic medium should not be exceeded as limits for the local tolerability of organic solvents in infusions. The systemic tolerability of the solvents varies in a substance-specific manner. In general, solvents lead to irritation and inflammation of veins and to haemolysis. Surfactants have even stronger haemolytic activity and, moreover, may cause an anaphylactic shock reaction with a fatal outcome. It is therefore necessary to examine such formulations particularly critically, and a precondition for a decision in their favour is an appropriate benefits/risk assessment.
Another possibility, for which the possible uses are, however, only limited, is to develop presentations such as, for example, lipid emulsions or liposome formulations, but these are considerably more complicated and thus more costly than conventional solution formulations. The formulation of oil-in-water emulsions for the active ingredient propofol is likewise described in GB 1 472 793 and furthermore in DE-19 509 828-A1. Further examples of slightly soluble active ingredients are to be found in U.S. Pat. No. 4,168,308. The production of aqueous liposome dispersions as a possible formulation of slightly soluble medicinal substances is described in EP-A-0 560 138 for active ingredients of the dihydropyridine class. This makes the considerable technical complexity of these alternative formulations clear.
If such formulation problems become evident, frequently no development of slightly soluble active ingredients is carried out, or the development times for a formulation become markedly prolonged.
It is an object of the invention to provide a method with which it is possible to administer slightly soluble active ingredients in a simple manner and, at the same time, distinctly reduce the amount and concentration of excipients necessary (solvents, surfactants etc.) for the formulation by comparison with conventional formulations, or make them entirely unnecessary. The intention is furthermore to provide an apparatus with which it is possible to mix an active ingredient concentrate in a very short time completely with a diluting medium so that the active ingredient can reach the patient""s vein in dissolved form. The mixing apparatus to be developed for this purpose must meet additional requirements: the construction material chosen is expediently one which can be sterilized and with which no attrition takes place. The flow pathways are expediently designed and dimensioned so that no regions of low flow (dead spaces) result and the flow velocities produce vigorous mixing in the mixing apparatus even at low flow rates. In order to ensure that the infusion solution spends a short time between the mixing apparatus and the patient, the mixing apparatus should be attached in the vicinity of the infusion site. The pressure prevailing in the mixing apparatus should not exceed 1 bar.
The invention therefore relates to a method for the in situ formulation of a medicinal substance solution for parenteral administration, in which at least two metered part-streams are continuously combined with the aid of a mixer to an active ingredient-containing total volumetric flow, characterized in that the resulting medicinal substance solution is not in thermodynamic equilibrium, and in that the resulting total volumetric flow after mixing is 0.2 ml/h to 500 ml/h, preferably 5 ml/h to 500 ml/h.
A medicinal substance solution which is not in thermodynamic equilibrium within the meaning of the invention is a solution which, under the administration conditions, has a tendency to undergo a transition with a chemical or physical change into a lower-energy state. Such a chemical or physical change may consist of, for example, the active ingredient decomposing, for example through hydrolysis, oxidation or photolysis, or being precipitated. The formulation of the medicinal substance solution by combining the metered part-streams in the method of the invention takes place in such a way that the resulting medicinal substance solution is subject to no change compromising administration until it enters the human body.
In a preferred embodiment of the method, the two part-streams are combined in a mixing chamber volume of 0.2 xcexcl to 2 xcexcl, preferably 0.4 xcexcl to 1.5 xcexcl.
In another preferred embodiment of the method of the present invention, the metered part-streams comprise at least one active ingredient-containing solution and at least one active ingredient-free diluting medium, and the resulting solution, which is not in thermodynamic equilibrium, is a supersaturated medicinal substance solution.
The active ingredient-containing solution is preferably an organic or aqueous organic active ingredient concentrate, and the active ingredient-free diluting medium is an aqueous or aqueous organic diluting medium.
The active ingredient concentrate is formulated using suitable water-miscible organic solvents, mixtures thereof or mixtures with water, in each of which the particular active ingredient dissolves especially well. Preferred organic solvents are macrogols of various molecular weights, 1,2-propylene glycol, ethanol, glycerol, glycofurol, 2-pyrrolidone and glycol ethers. It is possible to add further excipients such as stabilizers (surfactants, complexing agents) or antioxidants, isotonicizing agents, agents to adjust the pH, inter alia, to the active ingredient concentrate. However, it is preferred not to add stabilizers or at least to considerably reduce the amount thereof. It is possible by choosing the optimal solvent advantageously to reduce the total amount of organic solvent required. The active ingredient concentrate should not exceed a viscosity of 500 mPas and is preferably in the range 50-150 mPas, in order to ensure the function of the mixer. Solvents of higher viscosity such as glycerol and higher molecular weight macrogols are therefore mixed with lower viscosity solvents such as ethanol, water, 1,2-propylene glycol or others.
The active ingredient concentrate is diluted using diluting media. These are water, physiological saline or other electrolyte solutions such as Ringer solution, Ringer lactate solution etc., glucose-, sorbitol-, mannitol- or other carbohydrate-containing solutions, volume replacement solutions (dextrans and derivatives thereof, gelatin and derivatives thereof, starch derivatives), serum derivatives and combinations or aqueous organic solvent mixtures with solvent concentrations of less than 30%, preferably less than 10%. Suitable solvents are the water-miscible solvents already mentioned, such as macrogol of varying molecular weight, 1,2-propylene glycol, ethanol, glycerol, glycofurol, 2-pyrrolidone and glycol ethers. It is possible to add further excipients such as stabilizers (surfactants, complexing agents) or antioxidants, isotonicizing agents, agents to adjust the pH, inter alia, to the diluting medium. However, it is preferred not to add stabilizers or at least to considerably reduce the amount thereof. The viscosity of the diluting medium is preferably in the range 1-10 mPas, because this reduces the viscosity of the complete mixture and that of blood is approached.
For the purpose of the present invention, the supersaturated medicinal substance or active ingredient solution formed on mixing the active ingredient concentrate and diluting medium contains more dissolved active ingredient than the maximum amount of active ingredient which can be taken up by a solution of the same volume in thermodynamic equilibrium at the same temperature. The latter is the solubility of the active ingredient in the resulting infusion solution at the given temperature.
The result of mixing active ingredient concentrate and diluting medium is an infusion solution of the desired concentration, in which the active ingredient is present in dissolved but supersaturated form and does not crystallize out over the period from mixing until entry into the vein. In the vein there is rapid dilution by the bloodstream and binding to plasma proteins, which acts to counter crystallization of the active ingredient there. The concentration of solvents in the complete solution can be reduced to distinctly less than 30%, and in some cases to 7%, leading to the expectation of good local tolerability. At the same time, the total volume of the infusion solution and thus the total amount of organic solvent and other excipients is kept low.
In a further embodiment of the invention, the active ingredient-containing solution is an aqueous or aqueous organic active ingredient concentrate, and the active ingredient-free diluting medium is an aqueous or aqueous organic diluting medium, the pH values of which are matched together so that the total volumetric flow resulting after the mixing has a physiologically tolerated pH in the range from 3 to 10, preferably 5-8.
This embodiment is used in cases where the active ingredient has a pH-dependent solubility or stability, and the solubilities or stabilities are good only in nonphysiological pH ranges below pH 3 and above pH 10. An appropriately acid or alkaline aqueous or aqueous organic active ingredient concentrate is then prepared.
It is preferable to add to the active ingredient concentrate further excipients such as stabilizers (surfactants, complexing agents, solubilizers), water-miscible organic solvents or antioxidants, isotonicizing agents, buffering agents and others. However, it is preferred not to add stabilizers and organic solvents or at least to considerably reduce the amount thereof.
Aqueous diluting media whose pH has in each case been adjusted to counter the active ingredient concentrate are used to dilute the acidic or alkaline active ingredient concentrate. These diluting media are water, physiological saline or other electrolyte solutions such as Ringer solution, Ringer lactate solution etc., glucose-, sorbitol-, mannitol- or other carbohydrate-containing solutions, volume replacement solutions (dextrans and derivatives thereof, gelatin and derivatives thereof, starch derivatives), serum derivatives and combinations or aqueous organic solvent mixtures with solvent concentrations of less than 30%, preferably less than 10%. Suitable solvents are the water-miscible solvents already mentioned, such as macrogol of varying molecular weight, 1,2-propylene glycol, ethanol, glycerol, glycofurol, 2-pyrrolidone and glycol ether. It is possible to add further excipients such as stabilizers (surfactants, complexing agents) or antioxidants, isotonicizing agents, buffering agents, inter alia, to the diluting medium. However, it is preferred not to add stabilizers or at least to considerably reduce the amount thereof. The viscosity of the diluting medium is preferably in the range 1-10 mPas, because this reduces the viscosity of the complete mixture and that of blood is approached.
The combination of the active ingredient concentrate and diluting medium results in the pH of the complete solution being maintained at physiologically tolerated pH values in the range from 3 to 30, preferably in the range from 5 to 8.
The method of the invention is particularly suitable for the administration of active ingredients having a solubility of less than 1% by weight in water at 20xc2x0 C.
The active ingredient is preferably selected from the group consisting of dihydropyridines, anaesthetics, antibiotics, antimycotics, immunosuppressants, CNS-active drugs, oncologicals, steroids, barbiturates and vitamins.
Examples of such active ingredients are paclitaxel, docetaxel or substances related thereto, or ciclosporin.
The method is implemented by employing a mixer which preferably has no dead spaces and particularly preferably is miniaturized and has no dead spaces. The time spent by the mixture in the mixer and mixing section is expediently less than 1 min, preferably less than 30 s. The mixer expediently used is a nozzle mixer in which each of the part-streams is passed through a nozzle with a hydraulic diameter between 1 xcexcm and 500 xcexcm, preferably between 100 xcexcm and 250 xcexcm, and then collide with velocity components in opposite directions in a mixing chamber, and the mixture which forms is conveyed away as total volumetric flow. The total volumetric flow is expediently conveyed away through at least one aperture downstream of the mixing chamber. The nozzle diameter is expediently chosen so that the flow velocity in the nozzles is 0.01 to 15 m/s, preferably 0.01 to 3 m/s.
The invention furthermore relates to an apparatus for the in situ formulation of a medicinal substance solution for parenteral administration, having at least two feed lines, in each of which a reservoir and a metering device are connected in series, and the feed lines open downstream of the metering devices into an infusion line, characterized in that the feed lines are connected to a nozzle mixer which consists of a mixing chamber connected to the infusion line and of two nozzles which are disposed in the feed lines, are opposite to one another and open into the mixing chamber.
The mixing chamber has a volume of, preferably, 0.2 xcexcl to 2 xcexcl, particularly preferably of 0.4 xcexcl to 1.5 xcexcl, and the nozzles have a hydraulic diameter of, preferably, 1 xcexcm to 500 xcexcm, particularly preferably of 100 xcexcm to 250 xcexcm.
It is expedient for a homogenizing aperture with a hydraulic diameter of 1 to 500 xcexcm, preferably 100 to 250 xcexcm, to be disposed at the outlet from the mixing chamber.
The flow pathways within the two feed lines, including the metering devices and the nozzles, are preferably designed symmetrically.
The nozzle mixer preferably consists of an injection-mouldable plastic, particularly preferably of polycarbonate. When the apparatus according to the invention is used with photosensitive active ingredients, a substance which ensures adequate protection from light even with thin mixer walls can be admixed with the plastic. The substance is expediently selected in this case so that it effectively shields from the wavelength range in which the photosensitive active ingredient is decomposed.
The invention furthermore relates to an active ingredient administration kit for carrying out the method according to the invention, consisting of a pack with the apparatus according to the invention and of a reservoir at least for the active ingredient concentrate. The active ingredient administration kit preferably additionally contains tubing lines for the connections to the apparatus (mixer) and to the metering devices. Concerning the active ingredients, the active ingredient concentrates and the diluting media, reference may be made to the statements above.